NF-κB Activation Research Articles

Potential Strategies for Overcoming Drug Resistance Pathways Using Propolis and Its Polyphenolic/Flavonoid Compounds in Combination with Chemotherapy and Radiotherapy.

Conventional cancer treatments include surgical resection, chemotherapy, hyperthermia, immunotherapy, hormone therapy, and locally targeted therapies such as radiation therapy. Standard cancer therapies often require the use of multiple agents, which can activate nuclear factor kappa B (NF-κB) in tumor cells, leading to reduced cell death and increased drug resistance. Moreover, the use of multiple agents also contributes to added toxicity, resulting in poor treatment outcomes. Cancer cells gradually develop resistance to almost all chemotherapeutics through various mechanisms, such as drug efflux, alterations in drug metabolism and transport, changes in signal transduction pathways, enhanced DNA repair capacity, evasion of apoptosis, increased mutations, reactivation of drug targets, interaction with the cancer microenvironment, cancer cell-stroma interactions, epithelial-mesenchymal transition (EMT)-mediated chemoresistance, epigenetic modifications, metabolic alterations, and the effect of cancer stem cells (CSCs). Developing new strategies to improve chemotherapy sensitivity while minimizing side effects is essential for achieving better therapeutic outcomes and enhancing patients' quality of life. One promising approach involves combining conventional cancer treatments with propolis and its flavonoids. These natural compounds may enhance tumor response to treatment while reducing toxicity. Propolis and its components can sensitize cancer cells to chemotherapeutic agents, likely by inhibiting NF-κB activation, reprogramming tumor-associated macrophages (TAMs; an M2-like phenotype), and thereby reducing the release of matrix metalloproteinase (MMP)-9, cytokines, chemokines, and the vascular endothelial growth factor (VEGF). By reducing TAMs, propolis and its components may also overcome EMT-mediated chemoresistance, disrupt the crosstalk between macrophages and CSCs, inhibit the maintenance of stemness, and reverse acquired immunosuppression, thus promoting an antitumor response mediated by cytotoxic T-cells. This review highlights the potential of flavonoids to modulate the responsiveness of cancer to conventional treatment modalities. The evidence suggests that novel therapeutic strategies incorporating flavonoids could be developed to improve treatment outcomes. The positive effects of combining propolis with chemotherapeutics include reduced cytotoxicity to peripheral blood leukocytes, liver, and kidney cells. Therefore, polyphenolic/flavonoid components may hold potential for use in combination with chemotherapeutic agents in the clinical treatment of various types of cancers.

The inhibitory effect of salidroside on RANKL-induced osteoclast formation via NFκB suppression.

Bone fractures are a prevalent clinical issue, and recent studies highlighted the promising potential of natural bone healing agents in enhancing fracture repair and regeneration. The regulatory interaction mechanism between osteoblasts and osteoclasts is crucial for bone cell biology and bone disease. In Mongolian medicine, people have used the Rhodiola rosea (R. rosea) extract to accelerate bone healing in bone fractures. Salidroside is a bioactive compound of R. rosea. Salidroside is known to regulate bone metabolism and inhibit the activation of osteoclast cells, but how it affects the differentiation of osteoclasts is unknown. We examined the effect of R. rosea extract and its bioactive compound salidroside on the RANKL-induced osteoclast formation in RAW264.7 cells. The present study observed that salidroside directly inhibits RANKL-induced TRAP-positive osteoclast formation. Immunoblotting analysis revealed that salidroside inhibited the expression of c-Fos and NFATc1, osteoclastogenic key transcription factors, by suppressing late activation of p65 NFκB. Further, the ethanol extracts of R. rosea significantly reduced the RANKL-induced osteoclasts in a dose-dependent manner. In conclusion, salidroside inhibits RANKL-induced osteoclast formation via suppressing the NFκB/c-Fos/NFATc1 signalling pathway. R. rosea, a primary source of salidroside, is helpful for bone healing via its inhibitory effect on osteoclast formation.

Translating molecular insights into clinical success: alkaloid-based therapies for leukemia.

Alkaloids, a diverse class of naturally occurring compounds, have shown significant potential in the treatment of leukemia by targeting key molecular pathways and cellular mechanisms. This review discusses several potent alkaloids, such as homoharringtonine, chaetominine, matrine, and jerantinine B, which induce apoptosis, cell cycle arrest, and autophagy and inhibit signaling pathways including PI3K/Akt/mTOR, MAPK, and NF-κB. For instance, homoharringtonine induces apoptosis in acute myeloid leukemia (AML) cells via the SP1/TET1/5hmC/FLT3/MYC axis, while chaetominine enhances chemosensitivity by inhibiting the PI3K/Akt/Nrf2 pathway. In addition, targeting leukemia stem cells (LSCs) with alkaloids such as zalypsis offers promise due to its ability to induce apoptosis without significantly affecting normal hematopoietic stem cells. The modulation of the immune response, such as the inhibition of NF-κB activation by noscapine, further underscores the potential of alkaloids in overcoming treatment resistance. Various studies have demonstrated the efficacy of alkaloids across different leukemia types. For example, jerantinine B targets AML cells, while vincristine has shown success in lymphocytic leukemia. Clinical trials have also highlighted the benefits of alkaloids, including homoharringtonine, which achieved a 79.9% complete remission rate in AML patients. However, adverse effects such as neutropenia and hepatotoxicity necessitate careful management. Collectively, these findings emphasize the need for further research into alkaloid-based combination therapies to enhance efficacy and minimize toxicity, providing a promising avenue for innovative leukemia treatments.

Investigating the mechanisms of resveratrol in the treatment of gouty arthritis through the integration of network pharmacology and metabolics.

This study integrates network pharmacology and metabolomics techniques to explore the potential regulatory mechanisms of Res on gouty arthritis (GA). Network pharmacology was used to predict the mechanism of Res in regulating GA, and methods such as HE staining, ELISA, immunohistochemistry, Real-time PCR, Western blot, and molecular docking were used to verify the role of NF-κB, MAPK, and JAK/STAT inflammatory signaling pathways in the MSU-induced GA rat model. In addition, non-targeted metabolomics techniques were combined to further investigate the mechanism of Res in treating GA. The results of network pharmacology showed that Res may exert its therapeutic effects through the NF-κB signaling pathway. Animal experiments demonstrated that in the MSU-induced GA rat model, pathological damage, serum biochemical indicators, and levels of inflammatory factors were significantly increased, and the NF-κB signaling pathway was activated. The intervention of Res significantly reduced pathological damage, serum biochemical indicators, levels of inflammatory factors, and the activation of NF-κB, MAPK, and JAK/STAT signaling pathways in the model rats. Metabolomics results showed that Res could improve the metabolic trajectory deviations in serum and joint fluid of GA model rats. Through related metabolic pathway analysis, the most affected metabolic pathways were found to be Sphingolipid metabolism, Glycerophospholipid metabolism, Phenylalanine, tyrosine and tryptophan biosynthesis, Pantothenate and CoA, Citrate cycle (TCA cycle), and Arachidonic acid metabolism. Resveratrol can regulate the biosynthetic pathways of arachidonic acid, phenylalanine, tyrosine, and tryptophan, pantothenic acid and CoA biosynthesis pathways, TCA cycle, and other metabolic pathways, thereby regulating the NF-κB, MAPK, and JAK/STAT3 signaling pathways, and inhibiting the acute inflammatory response during GA attacks, showing characteristics of multi-pathway and multi-target action.

Investigating antibacterial and anti-inflammatory properties of synthetic curcuminoids.

The concept of intratumoral microbiota is gaining attention in current research. Tumor-associated microbiota can activate oncogenic signaling pathways such as NF-κB, thereby promoting tumor development and progression. Numerous studies have demonstrated that curcumin and its analogs possess strong antitumor effects by targeting the NF-κB signaling pathway, along with potent antibacterial properties. In this study, we tested the antibacterial activity of two curcuminoids, Py-cPen and V-cPen, against the Gram-negative bacterial strains Pseudomonas aeruginosa and Escherichia coli and the Gram-positive bacterial strain Streptococcus aureus using in vitro assays and fluorescent microscopy. We observed that both Py-cPen and V-cPen reduced NF-κB activation upon lipopolysacharide (LPS) challenge in cell assays. In addition, our findings indicate that Py-cPen and V-cPen interact with LPS, as demonstrated by transmission electron microscopy and confirmed using in silico analyses, thereby modulating LPS activity. Overall, our data indicate that Py-cPen and V-cPen exhibit strong antibacterial and antiinflammatory properties, suggesting their potential as candidates for new multitarget therapeutic strategies.

Poly-D,L-Lactic Acid Filler Attenuates Ultraviolet B-Induced Skin Pigmentation by Reducing Destruction of the Basement Membrane.

Poly-D,L-lactic acid (PDLLA) filler, which increases volume and collagen synthesis, is used for skin rejuvenation. PDLLA filler also increases M2 macrophages and IL-10. Ultraviolet (UV) radiation induces dermal hyperpigmentation by disrupting the basement membrane (BM), allowing melanin to move into the dermis. Therefore, using UV-irradiated macrophages and animal skin, we determined whether PDLLA filler decreased M1 macrophages and skin inflammation, thereby reducing BM destruction and dermal hyperpigmentation. UV radiation increased the M1 macrophage marker CD86 and TNF-α expression, which was inhibited by the treatment of macrophages with PDLLA. In fibroblasts treated with conditioned medium from UV-irradiated macrophages, NF-κB activity, NLRP3 inflammasome components (NLRP3, ASC, and pro-caspase-1), IL-18, MMP2, and MMP9 increased, but all decreased after PDLLA treatment. Similar to the in vitro study, UV-irradiated mouse skin showed increased CD86, NLRP3, ASC, pro-caspase-1, MMP2, and MMP9, which decreased after PDLLA injection. Disruption of the lamina densa of the BM and dermal pigmentation increased after UV irradiation and decreased after PDLLA injection. In conclusion, PDLLA reduced dermal pigmentation by decreasing BM destruction in UV-irradiated skin. PDLLA has the potential to reduce dermal pigmentation by regenerating the BM.

Galactooligosaccharides and Limosilactobacillus reuteri synergistically alleviate gut inflammation and barrier dysfunction by enriching Bacteroides acidifaciens for pentadecanoic acid biosynthesis

Ulcerative colitis (UC) is a debilitating inflammatory bowel disease characterized by intestinal inflammation, barrier dysfunction, and dysbiosis, with limited treatment options available. This study systematically investigates the therapeutic potential of a synbiotic composed of galactooligosaccharides (GOS) and Limosilactobacillus reuteri in a murine model of colitis, revealing that GOS and L. reuteri synergistically protect against intestinal inflammation and barrier dysfunction by promoting the synthesis of pentadecanoic acid, an odd-chain fatty acid, from Bacteroides acidifaciens. Notably, the synbiotic, B. acidifaciens, and pentadecanoic acid are each capable of suppressing intestinal inflammation and enhancing tight junction by inhibiting NF-κB activation. Furthermore, similar reduction in B. acidifaciens and pentadecanoic acid levels are also observed in the feces from both human UC patients and lipopolysaccharide-induced intestinal inflammation in pigs. Our findings elucidate the protective mechanism of the synbiotic and highlight its therapeutic potential, along with B. acidifaciens and pentadecanoic acid, for UC and other intestinal inflammatory disorders.

NIK Is a Mediator of Inflammation and Intimal Hyperplasia in Endothelial Denudation-Induced Vascular Injury.

Neointimal hyperplasia is the main cause of vascular graft failure in the medium term. NFκB is a key mediator of inflammation that is activated during neointimal hyperplasia following endothelial injury. However, the molecular mechanisms involved in NFκB activation are poorly understood. NFκB may be activated through canonical (transient) and non-canonical (persistent) pathways. NFκB-inducing kinase (NIK, MAP3K14) is the upstream kinase of the non-canonical pathway. We have now explored the impact of NIK deficiency on neointimal hyperplasia following guidewire-induced endothelial cell injury and on local inflammation by comparing NIK activity-deficient alymphoplasia mice (NIKaly/aly) with control wild-type (NIK+/+) mice. Guidewire-induced endothelial cell injury caused neointimal hyperplasia and luminal stenosis and upregulated the local expression of NIK and the NFκB target chemokines monocyte chemoattractant protein-1 (MCP-1/CCL2) and chemokine ligand 5 (RANTES/CCL5). Immunohistochemistry disclosed the infiltration of the media and intima by F4/80 positive macrophages. The intima/media ratio and percentage of stenosis were milder in the NIKaly/aly than in the NIK+/+ mice. Additionally, the gene expression for MCP-1 and RANTES was lower and F4/80+ cell infiltration was milder in the NIKaly/aly than in the NIK+/+ mice. Finally, circulating MCP-1 levels were lower in the NIKaly/aly than in the NIK+/+ mice, reflecting milder systemic inflammation. In conclusion, NIK is a driver of vascular wall inflammation and stenosis following guidewire-induced endothelial cell injury. NIK targeting may be a novel therapeutic approach to limit arterial stenosis following endothelial cell injury.

NF-κB in Thyroid Cancer: An Update.

The dysregulated NF-κB basal activity is a common feature of human thyroid carcinomas, especially in poorly differentiated or undifferentiated forms that, even if rare, are often resistant to standard therapies, and, therefore, are uncurable. Despite the molecular mechanisms leading to NF-κB activation in thyroid cancer being only partially understood, during the last few years, it has become clear that NF-κB contributes in different ways to the oncogenic potential of thyroid neoplastic cells. Indeed, it enhances their proliferation and viability, promotes their migration to and colonization of distant organs, and fuels their microenvironment. In addition, NF-κB signaling plays an important role in cancer stem cells from more aggressive thyroid carcinomas. Interfering with the different upstream and/or downstream pathways that drive NF-κB activity in thyroid neoplastic cells is an attractive strategy for the development of novel therapeutic drugs capable of overcoming the therapy resistance of advanced thyroid carcinomas. This review focuses on the recent findings about the key functions of NF-κB in thyroid cancer and discusses the potential implications of targeting NF-κB in advanced thyroid carcinomas.

CD24 regulates liver immune response and ameliorates acute hepatic injury through controlling hepatic macrophages.

Liver injury releases danger-associated molecular patterns, which trigger the immune response. CD24 negatively regulates the immune response by binding with danger-associated molecular patterns, but the specific role of CD24 in modulating macrophage-related inflammation during liver injury remains largely unexplored. Here, we aimed to investigate the mechanisms of macrophage CD24 in the development of liver injury. Our results show that CD24 expression is upregulated primarily in hepatic macrophages (HMs) during acute liver injury. CD24-deficient mice exhibited more severe liver injury and showed a significantly higher frequency and number of HMs, particularly Ly6Chi monocyte-derived macrophages. Mechanistically, the CD24-Siglec-G interaction plays a vital role in mitigating acute liver injury. CD24-mediated inhibitory signaling in HMs primarily limits downstream NF-κB and p38 MAPK activation through the recruitment of SHP1. Our work unveils the critical role of macrophage CD24 in negatively regulating innate immune responses and protecting against acute liver injury, thus providing potential therapeutic targets for liver-associated diseases.

Propolis Extract Attenuates NF-κB Activation and Chronic Kidney Disease Progression in a Rat Model: Potential Surgical Adjuvant?

Background: Chronic kidney disease (CKD) is a global health concern often complicated by cardiovascular diseases like atherosclerosis. Both conditions share an inflammatory pathogenesis, with nuclear factor kappa B (NF-κB) playing a central role. Propolis, a natural bee product with anti-inflammatory properties, has shown potential in mitigating CKD progression. This study aimed to investigate the effects of propolis extract on NF-κB activation in a rat model of CKD, exploring its potential benefits as a surgical adjuvant. Methods: Male white rats (Rattus norvegicus) were divided into three groups: a control group, a CKD group, and a CKD+Propolis group receiving propolis extract (200 mg/kg body weight) daily for 20 days. CKD was induced using the unilateral ureteral obstruction (UUO) method. NF-κB levels were measured weekly using ELISA. Results: Propolis extract significantly reduced NF-κB levels in the CKD+Propolis group compared to the CKD group (p<0.05). This effect was consistently observed across all time points, indicating a sustained reduction in NF-κB activation with propolis treatment. Conclusion: Propolis extract effectively attenuates NF-κB activation in a rat model of CKD, suggesting its potential as an adjunctive therapy for CKD management, particularly in the context of surgical interventions. Further research is needed to elucidate the underlying mechanisms and evaluate its efficacy in human subjects.

NF-κB in Alzheimer's Disease: Friend or Foe? Opposite Functions in Neurons and Glial Cells.

Alzheimer's disease (AD) is a devasting neurodegenerative disease afflicting mainly glutamatergic neurons together with a massive neuroinflammation mediated by the transcription factor NF-κB. A 65%-plus increase in Alzheimer's patients by 2050 might be a major threat to society. Hallmarks of AD are neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau and amyloid beta (Aβ) plaques. Here, we review the potential involvement of transcription factor NF-κB by hereditary mutations of the tumor necrosis factor pathway in AD patients. One of the greatest genetic risk factors is APOE4. Recently, it was shown that the APOE4 allele functions as a null allele in human astrocytes not repressing NF-κB anymore. Moreover, NF-κB seems to be involved in the repair of DNA double-strand breaks during healthy learning and memory, a function blunted in AD. NF-κB could be a friend to healthy neurons by repressing apoptosis and necroptosis. But a loss of neuronal NF-κB and activation of glial NF-κB in AD makes it a foe of neuronal survival. Hopeful therapies include TNFR2 receptor bodies relieving the activation of glial NF-κB by TNFα.

Impairment of neuronal tyrosine phosphatase STEP worsens post-ischemic inflammation and brain injury under hypertensive condition

Hypertension is associated with poor outcome and higher mortality in patients with ischemic stroke. The impairment of adaptive vascular mechanisms under hypertensive condition compromises collateral blood flow after arterial occlusion in patients with acute ischemic stroke resulting in hypoperfusion. The increased oxidative stress caused by hypoperfusion is thought to be a trigger for the rapid evolution of ischemic infarct volume under hypertensive condition. However, the cellular factors and pathways that contribute to the exacerbation of ischemic brain injury under hypertensive condition is not yet understood. The current study reveals that predisposition to hypertension leads to basal loss of function of the neuron-specific tyrosine phosphatase STEP, which plays a crucial role in neuroprotection against excitotoxic insult. The findings further show that a mild ischemic insult in hypertensive rats triggers an early onset and sustained activation of the neuronal extracellular signal regulated kinase (ERK MAPK), a member of the mitogen activated protein kinase family and a substrate of STEP. This leads to rapid increase in the activation of neuronal NF-κB, expression of neuronal cyclooxygenase-2 and subsequent biosynthesis of the pro-inflammatory mediator prostaglandin E2, resulting in rapid morphological transformation of microglia to the pro-inflammatory state and subsequent exacerbation of ischemic brain injury. Restoration of STEP signaling with intravenous administration of a STEP-derived peptide mimetic reduces the pro-inflammatory response in neurons, activation of microglia, and ischemic brain injury. The findings suggest that the basal loss of STEP function under hypertensive condition contributes to the exacerbation of ischemic brain injury by enhancing post-ischemic inflammatory response. The study not only presents a novel role of STEP in regulating neuroimmune communication but also highlights the therapeutic potential of a STEP-mimetic in mitigating ischemic brain damage under hypertensive condition.

Prognostic Impact of Microbiome Dysbiosis: A Prospective Study.

To determine the relationship between microbiome dysbiosis indices and biofilm immunogenicity and their prognostic implications on periodontal treatment response. Thirty periodontally healthy controls and 30 periodontitis cases (stage III) were recruited. Cases received non-surgical periodontal therapy (NSPT), and their treatment response at 6 months was evaluated using a treat-to-target endpoint (≤ 4 sites with probing depths ≥ 5 mm). Pooled subgingival biofilm samples were obtained from controls and cases. The V3-4 hypervariable region of the 16S rRNA gene was sequenced and two compositional indices (subgingival microbiome dysbiosis index, SMDI, and dysbiosis ratio, DR) were calculated. Nuclear factor kappa-B (NF-κB) activation elicited by biofilm samples in monocytic reporter cells was quantified to assess biofilm immunogenicity. SMDI, DR and biofilm immunogenicity were highly diagnostic for periodontitis (area under curves [AUC] > 0.90, p < 0.001). Among periodontitis cases, all three microbial parameters were significantly reduced after NSPT (p < 0.001). Cases achieving the treat-to-target endpoint had lower pre-treatment SMDI and biofilm immunogenicity (p < 0.05) and different microbial recolonization patterns from poor responders. Both measures predicted treatment response (AUC of 0.767 and 0.835, respectively, p < 0.05). Subgingival biofilm dysbiosis quantified using SMDI and biofilm immunogenicity was diagnostic of periodontitis and predictive of NSPT outcomes.

Anti-inflammatory Fatty Acid Derivatives From Mangrove-derived Actinomycetes Streptomyces sp.

Mangrove-derived actinomycetes are prolific chemical sources of complex and novel natural products, providing an excellent chance for new drug discovery. The chemical investigation of the mangrove-derived Streptomycessundarbansensis 06037, led to the discovery of two previously undescribed enone fatty acids (1-2), one new phenylpropionate derivate (3), along with the isolation of the ten known components (4-13). Those chemical structures of isolates were elucidated on the basis of the analysis of diverse spectroscopic data. Initial anti-inflammatory tests of 1-3 in lipopolysaccharide (LPS)-activated RAW 264.7 murine macrophage cells revealed that compound 1 possess significant inhibitory effect on the production of Nitro oxidase (NO), with the IC50 value around 15.33 ± 1.32 μM, together with the suppression of NF-κB phosphorylation and reducing the release of oxygen species (ROS) in RAW 264.7 macrophages, those results indicated that compound 1 may exert its anti-inflammatory activity through a reduction in ROS level and the suppression of NF-κB activation pathway.

Mevastatin-Induced HO-1 Expression in Cardiac Fibroblasts: A Strategy to Combat Cardiovascular Inflammation and Fibrosis.

Mevastatin (MVS) is known for its anti-inflammatory effects, potentially achieved by upregulating heme oxygenase-1 (HO-1), an enzyme involved in cytoprotection against oxidative injury. Nonetheless, the specific processes by which MVS stimulates HO-1 expression in human cardiac fibroblasts (HCFs) are not yet fully understood. In this study, we found that MVS treatment increased HO-1 mRNA and protein levels in HCFs. This induction was inhibited by pretreatment with specific inhibitors of p38 MAPK, JNK1/2, and FoxO1, and by siRNAs targeting NOX2, p47phox, p38, JNK1, FoxO1, Keap1, and Nrf2. MVS also triggered ROS generation and activated JNK1/2 and p38 MAPK, both attenuated by NADPH oxidase or ROS inhibitors. Additionally, MVS promoted the phosphorylation of FoxO1 and Nrf2, which was suppressed by p38 MAPK or JNK1/2 inhibitor. Furthermore, MVS inhibited TNF-α-induced NF-κB activation and vascular cell adhesion molecule-1 (VCAM-1) expression via the HO-1/CO pathway in HCFs. In summary, the induction of HO-1 expression in HCFs by MVS is mediated through two primary signaling pathways: NADPH oxidase/ROS/p38 MAPK, and JNK1/2/FoxO1 and Nrf2. This research illuminates the underlying processes through which MVS exerts its anti-inflammatory effects by modulating HO-1 in cardiac fibroblasts.

Vascular inflammaging: Endothelial CEACAM1 expression is upregulated by TNF-α via independent activation of NF-κB and β-catenin signaling.

Chronic inflammation with progressive age, called inflammaging, contributes to the pathogenesis of cardiovascular diseases. Previously, we have shown increased vascular expression of the Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in aged mice and humans, presumably via mutual upregulation with the pro-inflammatory cytokine TNF-α. CEACAM1 is critical for aging-associated vascular alterations like endothelial dysfunction, fibrosis, oxidative stress, and sustained inflammation and can be regarded as a main contributor to vascular inflammaging. This study was conducted to elucidate the mechanisms underlying endothelial CEACAM1 upregulation by TNF-α in detail. Using wildtype (WT) and TNF-α knockout (Tnf-/-) mice, we confirmed that the aging-related upregulation of endothelial CEACAM1 critically depends on TNF-α. The underlying mechanisms were analyzed in an endothelial cell culture model. TNF-α time-dependently upregulated CEACAM1 invitro. In pharmacological experiments, we identified an early NF-κB- and a delayed β-catenin-mediated response. Involvement of β-catenin was further substantiated by siRNA-mediated knockdown of the β-catenin-targeted transcription factor TCF4. Both signaling pathways acted independent from each other. Elucidating the delayed response, co-immunoprecipitation analysis revealed release of β-catenin from adherens junctions by TNF-α. Finally, TNF-α activated Akt kinase by increasing its Ser473 phosphorylation. Consequently, Akt kinase facilitated β-catenin signaling by inhibiting its degradation via phosphorylation of GSK3β at Ser9 and by increased phosphorylation of β-catenin at Ser552 that augments its transcriptional activity. Taken together, our study provides novel mechanistic insights into the aging-related, inflammation-mediated endothelial upregulation of CEACAM1. Beyond the pathogenesis of cardiovascular diseases, these findings may be significant to all fields of inflammaging.

Tobacco smoke exposure is a driver of altered oxidative stress response and immunity in head and neck cancer.

Exposomes are critical drivers of carcinogenesis. However, how they modulate tumor behavior remains unclear. Extensive clinical data link cigarette smoke as a key exposome that promotes aggressive tumors, higher rates of metastasis, reduced response to chemoradiotherapy, and suppressed anti-tumor immunity. We sought to determine whether smoke itself can modulate aggressive tumor behavior in head and neck squamous cell carcinoma (HNSCC) through reprogramming the cellular reductive state. Using established human and murine HNSCC cell lines and syngeneic mouse models, we utilized conventional western blotting, steady state and flux metabolomics, RNA sequencing, quantitative proteomics and flow cytometry to analyze the impact of smoke exposure on HNSCC tumor biology. Cigarette smoke persistently activated Nrf2 target genes essential for maintenance of the cellular reductive state and survival under conditions of increased oxidative stress in HNSCC regardless of HPV status. In contrast to e-cigarette vapor, conventional cigarette smoke mobilizes cellular metabolism toward oxidative stress adaptation, resulting in development of cross-resistance to cisplatin. In parallel, smoke exposure modulates both expression of PDL1 and the secretory phenotype of HNSCC cells through activation of NF-κB resulting in an altered tumor immune microenvironment (TIME) in syngeneic mouse models and altered PBMC differentiation that includes downregulated expression of antigen presentation and costimulatory genes in myeloid cells. Cigarette smoke exposome is a potent activator of the Nrf2 pathway and is a likely primary trigger for the tripartite phenotype of aggressive HNSCC consisting of: 1) reduced chemotherapy sensitivity, 2) enhanced metastatic potential and 3) suppressed anti-tumor immunity. The smoke exposome drives aggressive tumor behavior, treatment resistance and suppressed immunity through coordinated metabolic reprogramming. Successfully targeting this adaptation is critical to improving survival in smokers with head and neck cancer.

Literature review: nuclear factor kappa B (NF-κB) regulation in human cancers mediated by ubiquitin-specific proteases (USPs).

The nuclear factor kappa B (NF-κB) consists of a group of transcription factors of which its dysregulation is responsible for diseases such as inflammation and cancer. Ubiquitin-specific proteases (USPs) are the most prominent group among the deubiquitinases (DUBs). Their functions include control of protein stability and regulation of signaling transduction. The association between NF-κB activity and human cancer progression is evident. Still, the role of USPs in the NF-κB regulation in human cancers, especially prostate cancer, is not well understood. This review discusses on the role of USP-mediated regulation of the canonical NF-κB signaling pathway in human cancers and provides a prospect of future studies in prostate cancers. Within the biomedical literature database, PubMed, our review team searched for keywords including USP, NF-κB signaling pathway, cancer, prostate cancer, and specific USPs such as USP1, USP2, USP3, etc. These keywords were used individually or in combinations. After screening, only mechanistic studies and articles reporting the subsequent changes in cellular behaviors were included for full-text review. Most USPs function primarily as DUBs to regulate the canonical NF-κB signaling pathway. The typical K48- and K63-linked DUB activities of USPs are the best understood. These USPs are positive and negative regulators of the NF-κB activity. However, their DUB activities against polyubiquitin chains with atypical linkages have not yet been extensively studied. Furthermore, some USPs can regulate the canonical NF-κB signaling pathway via ubiquitin-independent mechanisms. In the regulation of the canonical NF-κB pathway, the USPs function primarily as DUBs, but they also regulate the p65/p50 by ubiquitin-independent mechanisms. Generally, in human cancer models, USP-mediated elevation and suppression of p65/p50 activity lead to more or less malignant cellular behaviors, respectively. Given the currently unbalanced focus on K48- and K63-linked DUB activities and the context-dependent function of USPs, future research of USP-mediated NF-κB regulation in human cancers should invest more in the DUB activities against the atypical polyubiquitin chains and test known mechanisms in different cancer models.

Molecular Mechanisms of Skatole-Induced Inflammatory Responses in Intestinal Epithelial Caco-2 Cells: Implications for Colorectal Cancer and Inflammatory Bowel Disease.

Inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), in intestinal epithelial cells significantly contribute to inflammatory bowel disease (IBD) and colorectal cancer (CRC). Given our previous findings that TNF-α is upregulated in intestinal epithelial Caco-2 cells induced by skatole, a tryptophan-derived gut microbiota metabolite, the present study aimed to explore the relationship between skatole and IL-6, alongside TNF-α. Skatole elevated the promoter activity of IL-6 as well as TNF-α, and increased IL-6 mRNA expression and protein secretion. In addition to activating NF-κB, the NF-κB inhibitor BAY 11-7082 reduced skatole-induced cell survival and the mRNA expression of IL-6 and TNF-α. NF-κB activation was attenuated by the extracellular signal-regulated kinase (ERK) pathway inhibitor U0126 and the p38 inhibitor SB203580, but not by the c-Jun N-terminal kinase (JNK) inhibitor SP600125. U126 and SB203580 also decreased the skatole-induced increase in IL-6 expression. When skatole-induced AhR activation was inhibited by CH223191, in addition to promoting NF-κB activation, IL-6 expression was enhanced in a manner similar to that previously reported for TNF-α. Taken together, these results suggest that skatole-elicited NF-κB activation induces IL-6 and TNF-α expression, although AhR activation partially suppresses this process. The ability of skatole to increase the expression of IL-6 and TNF-α may significantly affect the development and progression of these diseases. Moreover, the balance between NF-κB and AhR activation appears to govern the skatole-induced increases in IL-6 and TNF-α expression. Therefore, the present findings provide new insights into the mechanisms linking tryptophan-derived gut microbiota metabolites with colorectal disease.